G-protein coupled receptors (GPCRs) conduct the majority of transmembrane responses to hormones and neurotransmitters, and mediate the senses of sight, smell and taste. The β2 adrenergic receptor (β2AR) and the M2 muscarinic receptors are prototypical Family A GPCRs that mediates physiologic responses to autonomic nervous system activity. We have obtained three-dimensional structures of the β2AR and the M2 muscarinic receptor in inactive and active conformations, as well as a structure of the β2AR in complex with the G protein Gs. We have also used fluorescence, EPR and NMR spectroscopy to study the dynamic properties of the β2AR, and to map ligand-specific conformational changes. I will discuss what these studies have taught us about allosteric regulation of GPCR structure by G proteins and ligands.

Note: What are G-protein-coupled receptors?

When you are afraid, your heart beats faster, your blood pressure rises, and you breathe more heavily. This is partly the result of adrenaline forming in your body, which causes your heart rate to accelerate. Adrenaline is a hormone, a substance that manages communication between the cells in your body. Each cell has a small receiver known as a receptor, which is able to receive hormones.

What these receptors look like and how they work remained a mystery for many years. In order to track these receptors, in 1968 Robert Lefkowitz attached a radioactive isotope of the element iodine to different hormones. By tracking the radiation emitted by the isotope, he succeeded in finding a receptor for adrenaline, which allowed him to build an understanding of how it functions. In the 1980s, Brian Kobilka successfully identified the gene that regulates the formation of this receptor. The two researchers also discovered that the receptor was similar to receptors located in the eye that capture light. It was later discovered that there is an entire family of receptors that look and act in similar ways − known as G-protein-coupled receptors. Approximately half of all medications used today make use of this kind of receptor (source: www.nobelprize.org).